Quinazoline-2-Carboxamides as Selective PET Radiotracers for Matrix Metalloproteinase-13 Imaging in Atherosclerosis.

Matrix metalloproteinase-13 (MMP-13) plays a critical role in the progression of unstable atherosclerosis. A series of highly potent and selective MMP-13 inhibitors were synthesized around a quinazoline-2-carboxamide scaffold to facilitate radiolabeling with fluorine-18 or carbon-11 positron-emitting nuclides and visualization of atherosclerotic plaques. In vitro enzyme inhibition assays identified three compounds as promising radiotracer candidates. Efficient automated radiosyntheses provided [11C]5b, [11C]5f, and [18F]5j and enabled pharmacokinetic characterization in atherosclerotic mice. The radiotracers displayed substantial differences in their distribution and excretion. Most favorably for vascular imaging, [18F]5j exhibited low uptake in metabolic organs with minimal retention of myocardial radioactivity, substantial renal clearance, and high metabolic stability in plasma. Ex vivo aortic autoradiography and competition studies revealed that [18F]5j specifically binds to MMP-13 within atherosclerotic plaques and localizes to lipid-rich regions. This study demonstrates the utility of the quinazoline-2-carboxamide scaffold for MMP-13 selective positron emission tomography (PET) radiotracer development and identifies [18F]5j for imaging atherosclerosis.

Synthesis and Evaluation of [11C]MCC950 for Imaging NLRP3-Mediated Inflammation in Atherosclerosis.

Overexpression of the NLRP3 inflammasome has been attributed to the progressive worsening of a multitude of cardiovascular inflammatory diseases such as myocardial infarction, pulmonary arterial hypertension, and atherosclerosis. The recently discovered potent and selective NLRP3 inhibitor MCC950 has shown promise in hindering disease progression, but NLRP3-selective cardiovascular positron emission tomography (PET) imaging has not yet been demonstrated. We synthesized [11C]MCC950 with no-carrier-added [11C]CO2 fixation chemistry using an iminophosphorane precursor (RCY 45 ± 4%, >99% RCP, 27 ± 2 GBq/µmol, 23 ± 3 min, n = 6) and determined its distribution both in vivo and ex vivo in C57BL/6 and atherogenic ApoE-/- mice. Small animal PET imaging was performed in both strains following intravenous administration via the lateral tail vein and revealed considerable uptake in the liver that stabilized by 20 min (7-8.5 SUV), coincident with secondary renal excretion. Plasma metabolite analysis uncovered excellent in vivo stability of [11C]MCC950 (94% intact). Ex vivo autoradiography performed on excised aortas revealed heterogeneous uptake in atherosclerotic plaques of ApoE-/- mice in comparison to C57BL/6 controls (48 ± 17 %ID/m2 vs 18 ± 8 %ID/m2, p = 0.002, n = 4-5). Treatment of ApoE-/- mice with nonradioactive MCC950 (5 mg/kg, iv) 10 min prior to radiotracer administration increased uptake in the intestine (5.3 ± 1.8 %ID/g vs 11.0 ± 3.7 %ID/g, p = 0.04, n = 4-6) and in aortic lesions (48 ± 17 %ID/m2 vs 104 ± 15 %ID/m2, p = 0.0002, n = 5) by 108% and 117%, respectively, without significantly increasing plasma free fraction (fp, 1.3 ± 0.4% vs 1.7 ± 0.8%, n = 2). These results suggest that [11C]MCC950 uptake demonstrates specific binding and may prove useful for in vivo NLRP3 imaging in atherosclerosis.

Using the Women Empowerment in Livestock Index (WELI) to Examine Linkages between Women Smallholder Livestock Farmers' Empowerment and Access to Livestock Vaccines in Machakos County of Kenya: Insights and Critiques.

Livestock diseases are a major barrier to productivity for both male and female livestock keepers in Africa. In Kenya, two of the most devastating livestock diseases are Newcastle Disease (ND) in poultry and Contagious Caprine Pleuropneumonia (CCPP) in goats. Female livestock keepers tend to own more small ruminants (goats, sheep, etc.) and poultry and their livelihoods are adversely affected if their herds are not vaccinated against these diseases. Livestock farming has gender specific challenges and opportunities, with implications for the empowerment of women smallholder farmers, their household well-being, food security, and livelihoods. There is a need to estimate the level to which women benefit personally, socially, and economically from keeping livestock, yet there are very few studies that can measure if livestock production does in fact empower women smallholder livestock farmers. This study was done to examine linkages between women's empowerment and access and control over livestock products and vaccines. The Women Empowerment in Livestock Index (WELI) tool, which was customized to include questions on livestock vaccine access, was used to capture baseline data on empowerment scores for women in Machakos county, Kenya, prior to implementation of animal health and vaccine test models. In total, 400 participants were surveyed in two wards of Machakos County, Kola and Kalama, which were purposively selected. Women's empowerment was mapped to three domains (3DE): intrinsic agency (power within), instrumental agency (power to), and collective agency (power with) measured against adequacy in 13 indicators. Our results indicate that the household structure (female headed or dual headed household), age of respondents and number of members in a household influence the adequacy score. Work balance was the most significant negative contributor to women's disempowerment. Women contributed the most to livestock productive activities and attained adequacy in this area compared to men, directly impacting the WELI score. Women smallholder livestock farmers report low CCPP and ND vaccination rates, minimal knowledge on livestock diseases, a lack of access to cold chain storage and rarely visited veterinarians. The WELI score was 0.81 indicating a high level of empowerment for women in this community compared to men leading us to conclude that the overall WELI score was not an accurate indicator of women's empowerment in Machakos County. However, the decomposability of the index allows us to disaggregate the drivers of change and to examine how individual indicators contribute to disempowerment.

Gendered Barriers and Opportunities for Women Smallholder Farmers in the Contagious Caprine Pleuropneumonia Vaccine Value Chain in Kenya.

Most rural women smallholder farmers in Kenya generate income from the sale of small ruminant animals. However, diseases such as Contagious Caprine Pleuropneumonia (CCPP) prevent them from optimizing earnings. A crucial aspect for the control of CCPP is vaccination. In Kenya, CCPP vaccines are distributed through a government delivery mechanism. This study examines gaps and barriers that prevent women smallholder farmers from accessing CCPP vaccines. Qualitative data collection tools used were focus groups discussions, focus meals, jar voices and key informant interviews. Using outcome mapping (OM) methodology, critical partners and stakeholders in the CCPP vaccine value chain (CCPP-VVC) were identified to be the manufacturers, importers, distributors, agrovets, public and private veterinarians, local leaders, and farmers. Respondents highlighted the barriers to be limited access to vaccines due to cold chain problems, inadequate and late delivery of services, lack of information and training on vaccines, and financial constraints. Identified opportunities that can support women's engagement in the CCPP-VVC are the Kenya Governments two-third gender rule, which requires that not more than two thirds of the members of elective or appointive bodies shall be of the same gender, and positive community perception of female veterinarians. We conclude that more resources and training should be made available to women farmers, and that gender perspectives on policy development related to livestock production and disease prevention are urgently needed to improve livestock productivity and increase agency for women.